1. Field of the Invention
The present invention relates to compounds which bind to opioid receptors. In a preferred embodiment of the invention, the compounds are opioid receptor antagonists. The present invention also provides methods to treat conditions which are mediated by an opioid receptor.
2. Description of the Background
The opioid receptor system has been extensively investigated, and thousands of compounds have been synthesized and evaluated in radioligand binding assays, tissue assays, and animal models.1 Numerous structural types of opioid agonists have been discovered, and several such as methadone, meperidine, fentanyl, and pentazocine as well as others have become important drugs for the treatment of pain.1 In contrast, there are only a few structural types that show potent, opioid pure antagonist activity.1 The demonstrated effectiveness of opioid antagonists for the treatment of other substances of abuse as well as potential use in treatment of obesity depression and other CNS disorders has spurred new interest in the development of novel antagonists for opioid receptors.1,2 
Mounting evidence suggests that the endogenous kappa opioid system is involved in stress, depression, and other CNS disorders. Since stress and depression are both involved in relapse to substance abuse (cocaine, heroin, methamphetamine, nicotine, and alcohol) kappa antagonists will be useful in treating substance abuse relapse. In addition, the fact that the endogenous kappa opioid system opposes the actions of mu agonists suggests that antagonists selective for the kappa receptor system could suppress or eliminate the symptoms of withdrawal, which arise from an overactive kappa receptor system and thus could promote abstinence and prevent relapse. Therefore, the development of novel kappa antagonists possessing improved pharmacokinetic profiles would be of great value.
The oxymorphone-related compounds such as naloxone (1a) and naltrexone (1b) (FIG. 1), where the antagonist activity is dependent upon the N-substituent, have received considerable attention over the past few decades.1 Naloxone (1a) is used as an approved drug to treat heroin overdose and to reverse respiratory depression caused by morphine.2 Naltrexone (1b) is used to treat heroin and alcohol abuse.1 Pioneering studies by Portoghese and coworkers lead to the development of the prototypical kappa and delta opioid receptor antagonists, naltrindole (2, NTI), norbinaltorphimine (3, nor-BNI), and GNTI (4).5-6 More recently, we discovered the selective kappa opioid receptor antagonist JDTic (5), which is derived from the N-substituted trans-3,4-dimethyl-(3-hydroxyphenyl)piperidine class of pure antagonist.7-13 
Zimmerman et al. reported that trans-4a-aryldecahydroisoquinoline analogs possessed high affinity for the μ and κ opioid receptors and were potent analgesics in animal assays.14 The effect of varying the N-substituent in the trans-4a-aryldecahydroisoquinoline paralleled, to a certain extent, previous findings with other morphine part structures. Replacement of N-methyl with a phenethyl group significantly increased analgesic potency. The N-cyclopropylmethyl analogue was found in rodents to have mixed agonist-antagonist properties; however, its antagonist activity was far weaker than those reported for the N-(cyclopropylmethyl)morphinan and benzomorphan derivatives. In this application, we present methods to synthesize N-substituted 4a-(3-hydroxyphenyl)-8a-methyloctahydroisoquinolines and present test data that show these compounds to be potent opioid pure antagonists.